The long range objectives of this research program are to understand the biological role in health and disease of the two partner dihydroxylated vitamin D metabolites, namely 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24R,25-dihydroxyvitamin D3 (24,25-(OH)2D3). The principal immediate objectives of this research proposal are to study under in vivo conditions whether exogenously (drug) administered or endogenous levels of either 1,25(OH)2D3 or 24,25(OH)2D3 can modulate the biologic actions and pharmacokinetics of the partner dihydroxylated vitamin D metabolite. These studies will be carried out in four experimental groups: (a) normal volunteers; (b) in patients with stable chronic renal failure (CRF) or (c) end stage renal failure (ESRF) maintained on regular dialysis; and (d) intact dogs. The putative interactions of both endogenous and drug (exogenous) administered 1,25(OH)2D3 and 24,25(OH)2D3 on the counter metabolite will be evaluated in human subjects (groups a, b and c above) by monitoring intestinal Ca absorption, fecal Ca, blood levels of 1,25(OH)2D3, 24,25(OH)2D3, 1,24,25(OH)2D3, iPTH, Ca, P, Mg, alkaline phosphatase, and urinary Ca and cAMP excretion before and after dietary calcium or phosphate depletion and moderate phosphate loading. Also in groups (a,b,c, and d), treated as described in the preceeding sentence, a detailed application of compartmental analysis of the plasma disappearance curves after separate bolus i.v. administration of (3H)-1,25(OH)2D3 and (3H)-24,25-(OH)2D3 will permit quantitation of both the biological "production rate" (PR) and metabolic clearance rate (MCR) for 1,25(OH)2D3 and 24,25(OH2D3. Since the blood level of any steroid is governed by both its rate of biosynthesis and degradation, quantitative determinations of PR and MCR for these dihydroxylated vitamin D metabolites under the various stipulated physiological circumstances will permit a unique insight into their interactions and their capability for biologic actions.